全文获取类型
收费全文 | 1021篇 |
免费 | 96篇 |
专业分类
1117篇 |
出版年
2023年 | 11篇 |
2022年 | 31篇 |
2021年 | 32篇 |
2020年 | 22篇 |
2019年 | 32篇 |
2018年 | 25篇 |
2017年 | 29篇 |
2016年 | 36篇 |
2015年 | 74篇 |
2014年 | 87篇 |
2013年 | 82篇 |
2012年 | 94篇 |
2011年 | 72篇 |
2010年 | 51篇 |
2009年 | 46篇 |
2008年 | 48篇 |
2007年 | 51篇 |
2006年 | 62篇 |
2005年 | 40篇 |
2004年 | 38篇 |
2003年 | 45篇 |
2002年 | 42篇 |
2001年 | 6篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 6篇 |
1997年 | 2篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 4篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1969年 | 2篇 |
1963年 | 2篇 |
1961年 | 1篇 |
1957年 | 1篇 |
1950年 | 1篇 |
排序方式: 共有1117条查询结果,搜索用时 15 毫秒
991.
Camilla Fonseca Silva Tienne Aparecida do Nascimento Luciana Guimarães Keyller Bastos Borges Clebio Soares Nascimento Jr 《Chirality》2020,32(3):353-358
In this work, we have studied both experimentally and theoretically the praziquantel (PZQ) chiral discrimination. According to the main results, the enantioseparation of PZQ was efficiently optimized by HPLC on the reverse phase from the Chiralpak IB column, which has cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) as a chiral selector. The thermodynamic and structural parameters obtained via density functional theory (DFT) calculations pointed out the chiral discrimination as well as the enantiomeric elution order of PZQ, thus elucidating the experimental data and validating our proposed method. Finally, the hydrogen bonds and π-π stacking interactions played a key role in the discrimination between the PZQ diastereomeric complexes formed. 相似文献
992.
Opsins have evolved under the permanent heterozygote model: insights from phylotranscriptomics of Odonata 下载免费PDF全文
993.
Combined hybridization capture and shotgun sequencing for ancient DNA analysis of extinct wild and domestic dromedary camel 下载免费PDF全文
Elmira Mohandesan Camilla F. Speller Joris Peters Hans‐Peter Uerpmann Margarethe Uerpmann Bea De Cupere Michael Hofreiter Pamela A. Burger 《Molecular ecology resources》2017,17(2):300-313
The performance of hybridization capture combined with next‐generation sequencing (NGS) has seen limited investigation with samples from hot and arid regions until now. We applied hybridization capture and shotgun sequencing to recover DNA sequences from bone specimens of ancient‐domestic dromedary (Camelus dromedarius) and its extinct ancestor, the wild dromedary from Jordan, Syria, Turkey and the Arabian Peninsula, respectively. Our results show that hybridization capture increased the percentage of mitochondrial DNA (mtDNA) recovery by an average 187‐fold and in some cases yielded virtually complete mitochondrial (mt) genomes at multifold coverage in a single capture experiment. Furthermore, we tested the effect of hybridization temperature and time by using a touchdown approach on a limited number of samples. We observed no significant difference in the number of unique dromedary mtDNA reads retrieved with the standard capture compared to the touchdown method. In total, we obtained 14 partial mitochondrial genomes from ancient‐domestic dromedaries with 17–95% length coverage and 1.27–47.1‐fold read depths for the covered regions. Using whole‐genome shotgun sequencing, we successfully recovered endogenous dromedary nuclear DNA (nuDNA) from domestic and wild dromedary specimens with 1–1.06‐fold read depths for covered regions. Our results highlight that despite recent methodological advances, obtaining ancient DNA (aDNA) from specimens recovered from hot, arid environments is still problematic. Hybridization protocols require specific optimization, and samples at the limit of DNA preservation need multiple replications of DNA extraction and hybridization capture as has been shown previously for Middle Pleistocene specimens. 相似文献
994.
Englund C Steneberg P Falileeva L Xylourgidis N Samakovlis C 《Development (Cambridge, England)》2002,129(21):4941-4951
Oxygen delivery in many animals is enabled by the formation of unicellular capillary tubes that penetrate target tissues to facilitate gas exchange. We show that the tortuous outgrowth of tracheal unicellular branches towards their target tissues is controlled by complex local interactions with target cells. Slit, a phylogenetically conserved axonal guidance signal, is expressed in several tracheal targets and is required both for attraction and repulsion of tracheal branches. Robo and Robo2 are expressed in different branches, and are both necessary for the correct orientation of branch outgrowth. At the CNS midline, Slit functions as a repellent for tracheal branches and this function is mediated primarily by Robo. Robo2 is necessary for the tracheal response to the attractive Slit signal and its function is antagonized by Robo. We propose that the attractive and repulsive tracheal responses to Slit are mediated by different combinations of Robo and Robo2 receptors on the cell surface. 相似文献
995.
Pernille Hojman Jonas Fjelbye Bo Zerahn Jesper F. Christensen Christine Dethlefsen Camilla K. Lonkvist Claus Brandt Hanne Gissel Bente Klarlund Pedersen Julie Gehl 《PloS one》2014,9(9)
Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P<0.001), lean body mass (20.6%, P = 0.001), as well as anorexia, impaired muscle strength (22.5% decrease, P<0.001) and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P<0.001), maintained lean body mass (P<0.001) and muscle strength (P<0.001), reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival. 相似文献
996.
Tallheden T Bengtsson C Brantsing C Sjögren-Jansson E Carlsson L Peterson L Brittberg M Lindahl A 《Arthritis research & therapy》2005,7(3):R560-R568
Autologous chondrocyte transplantation (ACT) has been shown, in long-term follow-up studies, to be a promising treatment for
the repair of isolated cartilage lesions. The method is based on an implantation of in vitro expanded chondrocytes originating from a small cartilage biopsy harvested from a non-weight-bearing area within the joint.
In patients with osteoarthritis (OA), there is a need for the resurfacing of large areas, which could potentially be made
by using a scaffold in combination with culture-expanded cells. As a first step towards a cell-based therapy for OA, we therefore
investigated the expansion and redifferentiation potential in vitro of chondrocytes isolated from patients undergoing total knee replacement. The results demonstrate that OA chondrocytes have
a good proliferation potential and are able to redifferentiate in a three-dimensional pellet model. During the redifferentiation,
the OA cells expressed increasing amounts of DNA and proteoglycans, and at day 14 the cells from all donors contained type
II collagen-rich matrix. The accumulation of proteoglycans was in comparable amounts to those from ACT donors, whereas total
collagen was significantly lower in all of the redifferentiated OA chondrocytes. When the OA chondrocytes were loaded into
a scaffold based on hyaluronic acid, they bound to the scaffold and produced cartilage-specific matrix proteins. Thus, autologous
chondrocytes are a potential source for the biological treatment of OA patients but the limited collagen synthesis of the
OA chondrocytes needs to be further explained. 相似文献
997.
Bin Li Colin A. Flaveny Camilla Giambelli Dennis Liang Fei Lu Han Brian I. Hang Feng Bai Xin-Hai Pei Vania Nose Oname Burlingame Anthony J. Capobianco Darren Orton Ethan Lee David J. Robbins 《PloS one》2014,9(7)
Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. 相似文献
998.
Mia Roest Laursen Jakob Hansen Casper Elkjær Ninna Stavnager Camilla Bak Nielsen Kasper Pryds Jacob Johnsen Jan Møller Nielsen Hans Erik Bøtker Mogens Johannsen 《Metabolomics : Official journal of the Metabolomic Society》2017,13(6):67
Introduction
Remote ischemic conditioning (RIC) is a maneuver by which short non-lethal ischemic events are applied on distant organs or limbs to reduce ischemia and reperfusion injuries caused by e.g. myocardial infarct. Although intensively investigated, the specific mechanism of this protective phenomenon remains incompletely understood and in particular, knowledge on the role of small metabolites is scarce.Objectives
In this study, we aimed to study perturbations in the plasma metabolome following RIC and gain insight into metabolic changes by the intervention as well as to identify potential novel cardio-protective metabolites.Methods
Blood plasma samples from ten healthy males were collected prior to and after RIC and tested for bioactivity in a HL-1 based cellular model of ischemia–reperfusion damage. Following this, the plasma was analyzed using untargeted LC-qTOF-MS and regulated metabolites were identified using univariate and multivariate statistical analysis. Results were finally verified in a second plasma study from the same group of volunteers and by testing a metabolite ester in the HL-1 cell model.Results
The analysis revealed a moderate impact on the plasma metabolome following RIC. One metabolite, α-hydroxybutyrate (AHB) however, stood out as highly significantly upregulated after RIC. AHB might be a novel and more sensitive plasma-biomarker of transient tissue ischemia than lactate. Importantly, it was also found that a cell permeable AHB precursor protects cardiomyocytes from ischemia–reperfusion damage.Conclusion
Untargeted metabolomics analysis of plasma following RIC has led to insight into metabolism during RIC and revealed a possible novel metabolite of relevance to ischemic-reperfusion damage.999.
Ingfrid S. Haldorsen Mihaela Popa Tina Fonnes Nj?l Brekke Reidun Kopperud Nicole C. Visser Cecilie B. Rygh Tina Pavlin Helga B. Salvesen Emmet McCormack Camilla Krakstad 《PloS one》2015,10(8)
Background
Orthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics in vivo, with potential relevance for monitoring response to therapy.Methods
After orthotopic injection with luc-expressing endometrial cancer cells, eleven mice developed disease detected by weekly bioluminescence imaging (BLI). In parallel the same mice underwent positron emission tomography–computed tomography (PET-CT) and magnetic resonance imaging (MRI) employing 18F-fluorodeoxyglocose (18F-FDG) or 18F- fluorothymidine (18F-FLT) and contrast reagent, respectively. The mice were sacrificed when moribund, and post-mortem examination included macroscopic and microscopic examination for validation of growth of primary uterine tumours and metastases. PET-CT was also performed on a patient derived model (PDX) generated from a patient with grade 3 endometrioid endometrial cancer.Results
Increased BLI signal during tumour growth was accompanied by increasing metabolic tumour volume (MTV) and increasing MTV x mean standard uptake value of the tumour (SUVmean) in 18F-FDG and 18F-FLT PET-CT, and MRI conspicuously depicted the uterine tumour. At necropsy 82% (9/11) of the mice developed metastases detected by the applied imaging methods. 18F-FDG PET proved to be a good imaging method for detection of patient derived tumour tissue.Conclusions
We demonstrate that all imaging modalities enable monitoring of tumour growth and metastatic spread in an orthotopic mouse model of endometrial carcinoma. Both PET tracers, 18F-FDG and 18F-FLT, appear to be equally feasible for detecting tumour development and represent, together with MRI, promising imaging tools for monitoring of patient-derived xenograft (PDX) cancer models. 相似文献1000.